OVERALL SUMMARY AND SPECIFIC AIMS: NETWORK RESOURCE This component of the Mayo Clinic PGRN renewal application represents a request for the funding of a Network Resource designed to provide the entire PGRN with access to the latest techniques In the rapidly evolving field of Next Generation DNA sequencing. Access would be provided through a recurring, peer-reviewed process available to all PGRN Centers similar to the current PGRN-RIKEN process for obtaining access to pharmacogenomic GWAS genotyping through the PGRN-RIKEN collaboration. This proposed PGRN Nehwork Resource is one of three coordinated applications from current PGRN Centers, all with similar goals - clearly indicating an unmet need in pharmacogenomic research - a need emphasized by the letters of support from current PGRN Centers that are attached to this application. Those letters were sent by eight different PGRN research centers. Although pharmacoqenomics has always required access to DNA sequencing, that need has been accentuated bv recent dramatic changes in DNA seguencing technology and bv the eguallv dramatic outcomes of the application of genome-wide approaches to pharmacogenomics. Each of these proposals is designed to provide a link between the PGRN and a large, experienced Genomics Center with expertise in both the application and the evaluation of DNA sequencing technology. The issue is not whether pharmacogenomics as a discipline requires access to the very latest in rapidly evolving DNA sequencing techniques, but only how to achieve that goal in a way that will best advance the science while being affordable and open to all PGRN Centers. Specifically, the Mayo PGRN is proposing that a formal collaborative relationship be established with the Baylor College of Medicine (BCM)-Human Genome Sequencing Center (HGSC), one of three NHGRIsupported large genome centers - with an open, protocol-based selection process similar to the well established and highly successful PGRN-RIKEN process for the selection of PGRN pharmacogenomic GWAS genotyping projects performed in collaboration with RIKEN. The initial focus of the Mayo PGRN-sponsored Next Generation DNA sequencing Network Resource would be on sequencing large contiguous regions of the genome. In some cases, this will involve complete resequencing of large genes or tandemly repeated gene families or even entire gene families, e.g., the CYPome, all cytochrome P450 genes. In other cases, it wilt involve focused resequencing across SNP signals observed during pharmacogenomic GWA studies - in many cases, GWA studies made possible by the PGRN-RIKEN collaboration, thus building on a foundation established by that very successful program. Since the review panel for these applications will evaluate a series of Network Resource applications for access to Next Generation DNA sequencing, it should be emphasized that the Mayo PGRN looks upon these efforts as complementary. Therefore, it is possible that reviewers may conclude that some combination of these proposals should be supported. All of these proposals share; A recognition of the critical need for access to rapidly evolving DNA sequencing techniques in order to advance the science of pharmacogenomics. A recognition that established Genome Centers have the requisite experience, expertise and infrastructure required to make this effort succeed. A recognition that the process for access to Next Generation DNA sequencing will have to be open to all PGRN centers, based on scientific significance and feasibility. The cost associated with these studies would be covered primarily by funding available to the Network Resource.